Will the second time will be the charm for the diet drug Qnexa? The Food and Drug Administration (FDA) is reviewing the data on the weight-loss medication, again — an advisory panel will meet on Wednesday — having rejected the drug for approval once already in 2010.

The agency’s Endocrinologic and Metabolic Drugs Advisory Committee initially voted 10-to-6 against approving Qnexa over concerns that that it could increase heart rate and cause birth defects — concerns the FDA still has the second time around. According to the FDA’s briefing documents, the advisory panel will be asked on Wednesday to consider whether Qnexa’s maker, Vivus Inc., should conduct a clinical trial on cardiovascular risks prior to approval — a move that could significantly delay its reaching the market. Vivus proposes doing the study post-approval.

The key question for the panel isn’t whether Qnexa is effective for weight loss — clinical trials suggest it is, though in the second year of one trial, participants regained some of the weight they had lost in the first year — but whether its potential side effects outweigh its benefits.

Qnexa is a combination of two existing drugs — phentermine, an appetite-suppressing stimulant, and topiramate, an anti-seizure medication that is generally prescribed to control epilepsy but also affects appetite. The latter drug, topiramate, increases the risk of oral clefts, a birth defect, by two to five times when used by pregnant women, according to the latest studies, the FDA said.

To address those worries, Qnexa’s maker, Vivus Inc., had suggested approval of drug only for use in men and in women of non-childbearing age. That type of labeling work-around didn’t satisfy the FDA, however, and the agency asked the company to figure out a way to prevent pregnant women from using it.

Qnexa is not the first, nor will it be the last weight-loss pill to seek approval from the FDA. The market is ripe for a new drug to help Americans lose weight: “We really go from Weight Watchers to bariatric surgery when it comes to treatment options,” said Joseph Nadglowski, president of the Obesity Action Coalition, a patient advocacy group in Tampa, Fla., in an interview with Bloomberg. “For many, that’s a pretty big gap.”

But the FDA has a spotty history with diet drugs and an ever-rising bar for new weight-loss remedies. Following is a brief history of the diet drug industry’s successes, failures and near misses.

Amphetamines
The original diet drugs date back to the 1950s. Amphetamines worked simply by boosting metabolism all around, driving the body to burn more calories faster. The problem — as with any energy system pushed to its limits — was that cells aren’t made to burn, burn, burn. They eventually burn out, leading to heart problems, chest pains, palpitations, insomnia and other health issues.

Amphetamines, which boost energy and mood, are also addictive, since they tap into the brain’s reward system. After their potential for misuse emerged, U.S. and European officials banned most amphetamine-based medications, but the drug is still available, often hidden in South American diet remedies.

Fen-phen and Redux
A new combination of the existing appetite-suppressing drugs fenfluramine and phentermine, fen-phen was all the rage in the mid-1990s, leading to weight loss in hundreds of thousands of Americans. In 1996, after much media attention, the FDA approved a related drug, dexfenfluramine, as Redux, which did the same thing as fen-phen but with fewer side effects. Yet the side effects were still severe: in the summer of 1997, the FDA revealed that 82 patients had developed defects in their heart valves while on fen-phen, and that seven patients had come down with the same condition on Redux. Other patients developed pulmonary hypertension, a sometimes fatal lung condition, and a JAMA study confirmed earlier reports that both fen-phen and Redux caused brain damage in lab animals. After millions of prescriptions written, in 1997 both fenfluramine and Redux were pulled from the market.

Sibutramine (Meridia)
Since amphetamines carried too many risks of addiction and other side effects, researchers began focusing on ways to trick the brain into wanting less food. Sibutramine, approved in 1997, worked on brain chemicals that affect appetite: by blocking the reuptake of neurotransmitters such as norepinephrine and serotonin, the drug could suppress the desire to eat and convince the body that it was full, helping dieters lose 5% to 10% of their body weight in a few months. After studies showed users were at higher risk of developing heart problems and stroke, however, the medication was withdrawn from the market in 2010.

Lorcaserin (Lorqess)
Like sibutramine, lorcaserin focused on altering brain chemicals, specifically serotonin, to convince the body it was full. But an FDA panel recommended in 2010 against approving the drug because of studies in which female rats taking the drug developed a disturbing number of mammary tumors. The panel also asked Lorqess’s maker, Arena, to conduct additional tests on the drug’s effect on users with diabetes and heart disease, conditions that commonly affect those who are overweight.

Contrave
A combination of two previously approved drugs, the antidepressant medication bupropion and the anti-addiction pill naltrexone, Contrave got the green light from an FDA advisory panel, which voted 13-to-7 for approval in 2010, but was ultimately rejected by the agency itself over concerns that the drug raised the risk of heart attacks, strokes and other cardiovascular problems. The FDA said the minimal weight loss experienced by users (4.2%) didn’t justify the potential cardiovascular risks.

In another sign of the high threshold the FDA is setting for diet drugs, the agency said that Orexigen Therapeutics, Contrave’s maker, would need to conduct more extensive and long-term studies of the possible heart risks associated with Contrave, before approval would be considered. Such a clinical trial would cost the company hundreds of millions of dollars — enough to kill further development if Orexigen decides the anticipated diet-pill market doesn’t justify the cost.

Orlistat (Alli, Xenical)
Currently the only approved diet medication on the U.S. market, orlistat is available in both over-the-counter (Alli) and prescription (Xenical) formulations. Orlistat works not in the brain but in the gut, encouraging weight loss by preventing the body from absorbing the fat in food. The medication, which is meant to be used in combination with a low-fat diet and exercise program, can help users shed 50% more weight than they would with diet and exercise alone. Like all drugs, however, there are side effects — in this case, excess gas, oily or fatty stools and even oily spotting.

Alice Park is a writer at TIME. Find her on Twitter at @aliceparkny. You can also continue the discussion on TIME’s Facebook page and on Twitter at @TIME.